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 FINAL GRADE PROJECT 2014-­‐2015 On the way to cure Atrial Fibrillation. Radiofrequency ablation vs Cryoablation: Iatrogenic Atrial Septal Defect after ablation procedures. Marta Soriano Hervás TUTOR: Pedro Brugada Terradellas, Gian-­‐Battista Chierchia CO-­‐TUTOR: Josep Garré Electrophisiology department, Heart Rhythm Management Center, UZ Brussel F A C U L T A T D E M E D I C I N A D E L A U N I V E R S I T A T D E G I R O N A ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 2
“If you don’t go further than your front yard fence,
you will discover nothing”
Wright brothers
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 3
AKNOWLEDGEMENTS
I would like to express my gratitude to the Faculty of Medicine, University of
Girona, specially to Fabiana Scornik, and Professor Pedro Brugada, Head of
Heart Rhythm Management Centre UZ Brussel University Hospital who gave
me the opportunity of living this rewarding experience and working with this
amazing team of Cardiac Electrophysiologist at the UZ Brussel University
Hospital.
I would particularly like to thank Prof. Gian-Battista Chierchia for the continuous
revision of my work. His input assured the quality of this work.
Thanks also to Dr Jose Garre who has been my co-tutor from Girona
supervising my work, as well as Mª del Mar Castillo, whose review has been
essential for me.
How could I forget the UdG’s library support! Thank you so much for all the help
provided. All this work has been partly developed thanks to you.
Last but not least, I would like to thank for all the support and help provided by
Prof. Carlo de Asmundis and the fellows (Ghazala Irfan, Yukio Saitoh, Giuseppe
Ciconte, Giacomo Mugnai and Burak Hunuk), Freddy and the rest of nurses in
the electrophysiology laboratory.
It was really nice to meet you all and to spend these three months learning from
your specific techniques. Thank you so much.
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 4
CONTENTS
ABSTRACT ........................................................................................................ 5 ABBREVIATIONS .............................................................................................. 6 PART 1: INTRODUCTION ................................................................................. 7 1.BACKGROUND ................................................................................................... 7 1.2 DEFINITION OF ATRIAL FIBRILLATION ................................................................. 8 1.3 EPIDEMIOLOGY................................................................................................ 8 1.4 CLASSIFICATION OF AF.................................................................................... 9 1.5 PATHOPHYSIOLOGICAL MECHANISMS ................................................................ 9 1.6 MANAGEMENT OF AF..................................................................................... 11 2. JUSTIFICATION ................................................................................................ 15 PART 2: STUDY............................................................................................... 17 2.1 HYPOTHESIS ................................................................................................. 17 2.2 OBJECTIVE ................................................................................................... 17 2.3 MATERIAL AND METHODS............................................................................... 18 2.3.1 STUDY DESIGN ........................................................................................... 18 2.3.2 PARTICIPANTS ............................................................................................ 18 2.3.3 INCLUSION AND EXCLUSION CRITERIA ........................................................... 18 2.3.4 SAMPLE SIZE .............................................................................................. 19 2.3.5 VARIABLES AND MEASUREMENTS ................................................................. 20 2.3.6 STATISTICAL ANALYSIS ................................................................................ 24 2.4 ETHICAL CONSIDERATIONS ............................................................................ 24 2.5 RESULTS ...................................................................................................... 25 2.6 DISCUSSION .................................................................................................. 28 2.7 LIMITATIONS ................................................................................................. 31 2.8 CONCLUSION ................................................................................................ 31 2.9 CRONOGRAM ................................................................................................ 32 2.10 BUDGET ..................................................................................................... 33 BIBLIOGRAPHY .............................................................................................. 34 TABLES ........................................................................................................... 40 ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 5
ABSTRACT
Background. In recent years, Pulmonary Vein Isolation (PVI) has progressively increased its role
in the treatment of drug resistant Atrial Fibrillation (AF). Traditionally these procedures are performed
with a “point by point” ablation technique by means of radiofrequency (RF) energy; however, in the
last years, the use of novel alternative technologies such as cryothermal balloon (CB) ablation is
growing rapidly. Irrespective of the technique used, the first step in every PVI ablation is the access to
the left atrium (LA) through a transseptal puncture (TS). In the RF ablation procedure, LA access is
commonly achieved with a double TS puncture to insert both an ablation and a circular mapping
catheter. In the CB ablation procedure, only a single TS puncture is usually required.
Objective. Our aim was to compare the incidence of iatrogenic atrial septal defect (iASD) between
double transseptal conventional RF and CB ablation at 1-year follow-up evaluating its clinical
significance.
Methods. We analysed and compared the presence of iASD and its clinical repercussion in a
retrospective study of 127 patients, affected by drug resistant paroxysmal or early persistent AF, who
underwent PVI by the means of either RF or CB ablation, between January 2008 and December 2012
in UZ Brussels hospital. Transoesophageal echocardiography was performed before each procedure.
This study has been followed up for 1 year.
Results. The incidence of iASD at 1-year follow up following PVI was significantly higher in the CB
group (22.2% vs 8.5%; p=0.03). Mean iASD diameter was larger in the CB group (0.60x0.50cm vs
0.44x0.35cm) without statistical significance. Only left to right atrial shunt was observed. No adverse
events were recorded in these patients during the follow up.
Conclusion. The incidence of iASD at 1-year follow up following CB ablation procedure for PVI is
significantly higher with respect to RF procedures. Although no adverse clinical events were recorded
in patients with persistence of iASD, this complication should not be underestimated and systematic
echocardiographic examinations might be advised in all individuals exhibiting this finding.
Keywords: atrial fibrillation, iatrogenic septal defect, cryoballoon, radiofrequency.
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 6
ABBREVIATIONS
AAD Antiarrhythmic drugs
AF Atrial Fibrillation
ASI: Agitated saline injection
AV: atrioventricular
CI: confidence interval
CTGF: connective tissue growth factor
DCC: direct current cardioversion
HF: Heart failure
IASD: iatrogenic septal defect
LV: left ventricular
PAF Paroxysmal atrial fibrillation
PV pulmonary veins
PVI pulmonary veins isolation
QQL quality of life
SR: sinus rhithm
SVC: Superior vena cava
TEE: transesophageal examination
TSP: transseptal puncture
TTE: transthoracic examination
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 7
PART 1: INTRODUCTION
1.Background
Atrial fibrillation (AF) is the most common arrhythmia occurring in 1-2% of
general population. Over 6 million Europeans suffer from this arrhythmia, and
its prevalence is estimated to increase at least double in the next five decades
as the population age(1,2).
AF has frequent and severe consequences in affected patients. It is strongly
associated with increased morbidity and mortality(1). Its prevention and
treatment is one of the main goals of a cardiologist. Thus, the restoration and
maintenance of normal sinus rhythm correlate with improved quality of life in
these
patients(3).
The
arrhythmia
is
usually
easy
to
diagnose
electrocardiographically yet the “ideal” approach to the management of AF is
still questionable. Traditionally, the first-line treatment of AF has always been
pharmacological. Its desirable goal consists in restoring and maintaining sinus
rhythm in order to relieve the patient from symptoms and reduce the risk of
thromboembolic events. However, its effectiveness remains inconsistent. The
likelihood of AF recurrence within 6 to 12 months approaches 50% with most
drugs(3). These facts together with the finding of ectopic beats originating from
the pulmonary veins as one of the main sources of AF, have led to the
development of new invasive techniques to cure AF such as percutaneous
catheter ablation(1,3–5).
From all the techniques developed so far, radiofrequency ablation is the gold
standard(6). However, although it is an effective technique in maintaining sinus
rhythm, this technique is associated with long procedural times and is often
cumbersome(2). Besides, lesions created by hyperthermia, inevitably involve
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 8
some degrees of tissue disruption that increases the risk for perforation and
thromboembolic stroke(7,8). Therefore, as an alternative ablation treatment,
cryoballoon ablation has emerged. Cryothermic lesion offers minimal tissue
disruption and preserves basic underlying tissue architecture. In addition, it is
associated with a similar success rates if compared to RF, and might be less
time consuming(9) .
During the procedure, either cryoballoon ablation or RF, transseptal puncture
(TSP) is the first step to achieve transatrial access(10). Although it is extremely
safe in the majority of cases, TSP might be associated with minor and major
complications(11). Among them, it is the potential permanency of iatrogenic
septal defect (IASD)(10,12–14) . The aim of this study is to compare the incidence
and clinical outcomes of iASD in AF ablation using either RF or Cryoballoon at
one-year follow-up.
1.2 Definition of Atrial Fibrillation
AF is a supraventricular tachyarrhythmia characterized by uncoordinated atrial
activation with consequent deterioration of atrial mechanical function, which
leads to an increased long-term risk of stroke, heart failure (HF),
thromboembolism, and all cause excess mortality(1,15). Furthermore, the quality
of life of these patients is impaired(3).
1.3 Epidemiology
AF represents the most common tachyarrhythmia that occurs in humans, with
an incidence which almost doubles every decade after 55 years of age(1). This
results in a high prevalence of AF in individuals >70 years of age.
Approximately 70% are between 65 and 85 years old(1,16). As the population
ages, AF represents an important public health problem.
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 9
1.4 Classification of AF
Several classifications have been proposed for AF even though none fully
accounts for all aspects of this arrhythmia. One of the classification scheme
recommended consists of distinguishing a first-detected episode of AF, either if
it is or is not symptomatic or self-limited. It is recognized that there may be
uncertainty about the duration of the episode and about undetected episodes.
Every patient who presents with AF for the first time is considered a patient with
first diagnosed AF (irrespective the duration or the presence and severity of the
arrhythmia). If the patient has two or more episodes, AF is considered recurrent.
If it terminates in a spontaneous way (usually it is self-terminating within 48
hours), it is called paroxysmal atrial fibrillation (PAF). Although AF paroxysms
might continue for up to 7 days, the 48h timepoint is clinically important. When
an AF episode is sustained longer than 7 days or requires termination by
cardioversion, either with drugs or by direct current cardioversion (DCC), it is
called persistent AF. The category of persistent AF also includes cases of longstanding AF, usually referring to cases where the AF has lasted for more than
one year(1).
The importance of this classification lies largely in the success rate after
ablation. PAF’s ablation yields a higher success rate if compared to the
persistent, long-standing AF. This fact seems to be due to the reflection of an
earlier stage in the PAF arrhythmia(3,17).
1.5 Pathophysiological mechanisms
There are different mechanisms involved as a cause of AF. For instance, an
increased sympathetic or parsympathetic tone, or the replacement of atrial
myocytes by interstitial fibrosis, which can be caused by genetic defects,
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 10
inflammation, as well as structural changes associated with aging or atrial
dilatation in any type of heart disease (valvular disease, hypertension, HF,
coronary atherosclerosis)(1).
However, the onset and maintenance of AF is associated with focal
mechanisms involving automaticity and multiple reentrant wavelets(18).
The demonstration of automatic focus for AF has been an important discovery,
so the ablation of this source can extinguish AF, mainly PAF. The most frequent
source of triggering AF have been found in pulmonary veins (PV)(18). But, there
are also other foci found in the superior vena cava (SVC), ligament of Marshall,
left posterior free wall, crista terminalis, or coronary sinus(1,19).
As mentioned above, the most important structures that play a critical role in
triggering AF in most of cases are PVs. From an embryological standpoint, this
ectopic activity could be explained by the presence of pacemaker cells in PVs.
It is found that the PVs have the same origin as the other cardiac conduction
tissues and serve as foci of automaticity(20). There are also studies that show
the presence of transitional and Purkinje cells which are known to have intrinsic
electrical activity(18,21). Another hypothesis consists in the existence of slow
conduction areas in the proximal part of the pulmonary veins in comparison to
the adjacent left atrium. This fact suggest that on top of the ectopic activity,
these electrophysiological properties of the pulmonary vein sleeves, could
facilitate rapid re-entry and maintenance of AF(22).
Even though there are many factors involved in the onset and maintenance of
AF, the degree to which changes in atrial architecture contribute to the initiation
and maintenance of AF is not known. What it is currently known is that the
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 11
duration of episodes is correlated with a decrease in atrial refractoriness, and all
the
factors
mentioned
above
can
influence
to
that
abnormal
atrial
refractoriness(1).
1.6 Management of AF
Management of patients with AF consists in 3 different strategies(22):
 Ventricular rate control.
 Assessment of the need for anticoagulation in order to prevent
thromboembolism’s events.
 Correction of the rhythm disturbance.
Depending on the patient’s characteristics, the management strategy is
discussed: type and duration of AF, severity and type of symptoms, associated
cardiovascular disease, patient’s age, medical conditions, short and long-term
medical objectives, and pharmacological and nonpharmacological therapeutics
options.
As mentioned previously, antiarrhythmic drugs are used as first-line treatment
with the objective of maintaining sinus rhythm, thus avoiding long-term
anticoagulation, thromboembolic risk is reduced and survival is improved.
Although AAD might influence in the heart’s electrical activity avoiding the onset
and perpetuation of the AF, it is described that its long term effectiveness is
shown only in a minority of cases(15). Arrhythmias seem to recur within one to
two years in at least 50% of patients despite AAD therapy. Furthermore,
antiarrhtythmic drugs are also associated with cumulative adverse events over
time(3,4).
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 12
These deceiving results and the demonstration of ectopic beats originating from
the pulmonary veins have catalyzed the development of these invasive
techniques. These nonpharmacological approaches developed such as
percutaneous catheter ablation therapies pursue the challenge of curing
AF(21,23–26).
1.6.1 Ablation therapies
Even though, it is not yet considered as first-line treatment, AF ablation has
increasingly been used over the last decade. This is due to the demonstration
of its superiority compared to conventional AAD therapy in terms of arrhythmia
recurrence, quality of life, and arrhythmia progression(5,15,17). Furthermore,
according to a recent metanalysis, ablation is safer in terms of complications if
compared to AAD(27).
1.6.1.1 Main technologies for pulmonary vein isolation
Due to the increasing number of PVI procedures performed daily in
electrophysiological
laboratories
worldwide,
many
attempts
of
ablative
techniques are being developed in order to take AF safer and more
effective(24,26,28).
Radiofrequency versus cryoablation. Strenghts and limitations.
Currently, radiofrequency is the gold-standard for the catheter-based approach
to AF ablation(7,8,29). However, lesions created by hyperthermia (which is the
energy RF works with), inevitably involve some degree of tissue disruption that
increases the risk of perforation and thromboemolic stroke(30). In addition, this
cumbersome procedure uses a point-by-point technique, which makes difficult
to create continuous lines, therefore potencially leaving conduction gaps. These
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 13
gaps may facilitate recurrence of the arrhythmia. As an alternative treatment,
cryoablation has appeared, which works by freezing the tissue. The resultant
lesions preserve tissue’s architecture, maintain good tensile strength and are
minimally thromboembogenic. The latter consists in a functional destruction
preserving the structure(8,30). It is reported that cryoballon, delivering
cryothermal energy is able to achieve PVI in virtually all veins, with similar
success rate if compared to RF. Furthermore, it might be less time
consuming(31).
With any ablative technology, the acute endpoint of electrical isolation can be
achieved in almost 100% of veins at the end of all procedures. Nevertheless, a
mean 25-30% of individuals develop clinical recurrence on the medium-long
term follow-up after the first procedure(31,32). The most likely explanation of it is
electrical reconnection of the pulmonary veins(33). Another possible cause of
recurrence are the extrapulmonary vein foci(1,19,34). These foci, potencially
located anywhere in the atria can trigger AF in a minority of patients. However,
localizing these triggers is difficult and often time consuming. Therefore, due to
the abovementioned considerations, ablation of PAF mainly consists in PVI.
There are also other factors, which might explain the variety of outcomes(35,36).
First, the success of AF procedure is highly dependent on the operator’s skills
and the experience. Second, up to date there is still no consensus on how to
perform AF ablation(37). Third, the classification of AF might in some cases differ
with the electropathological stage of the disease. This fact could lead to classify
as PAF patients who are affected by a more advanced stage of the disease. It
is known that persistent and long standing persistent AF tend to reccur more
often after AF ablation(38). Another important factor that can lead to this
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 14
discrepancy is the non-standardized follow-up after PVI. In fact, many centers,
but not all, apply what is known as “blanking period”. This is a period of time
(normally around 2-3 months) when antiarrhythmic recurrence is not considered
clinically relevant(39,40). Furthermore, there is no consensus on post-ablation
antiarrythmic medication protocol. Some centers continue medication up to 6
months after the procedure and some prescribe medications only in case of
clinical recurrence. All these factors can have an impact on success rates.
Additionally, the time to repeat procedure in case of recurrence is also a matter
of debate(41).
Procedure and complications
Irrespective of the technique used, transseptal puncture (TSP), is the first step
of every AF ablation procedure (apart from channelling the chosen vein
(normally femoral vein) to reach the heart)(10). In the RF ablation procedure, left
atrial access is commonly achieved with a double TSP to insert both an ablation
and a circular mapping catheter. In the CB ablation procedure, only a single
TSP is required. Although extremely safe in the majority of cases in
experienced hands, TSP might be associated with minor and major
complications(42). Among them, there is the iatrogenic septal defect (IASD),
which is a small communication between both atria as a result of the
puncture(10,12–14). Although the clinical significance of persistent IASD has not
yet been well-defined, IASD with interatrial shunting might be associated to
paroxysmal embolism and stroke(14,43). It is also known that Patent Foramen
Ovale and Atrial Septal Defects have been related apart from paradoxical
embolism and cryptogenetic stroke, to left ventricular disfunction, pulmonary
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 15
hypertension, migraine, decompression sickness and platipnea-orthodesoxia
syndrome(44–46).
Finally, although the following listed complications have not been analysed in
the current study, it should be noted that could also occur. For instance,
pericardial effusion and tamponade, cerebral ischemic complications, PV
stenosis, atrium-esophageal fistule, phrenic nerve injury and left atrial
tachycardia(11). It should be highlighted that all these complications have been
already studied in previous studies. According to a recent survey conducted on
more than 9000 patients who underwent AF ablation, complications occurred in
roughly 4% of cases and not all centres were highly experienced(5). As it is
known, PVI is much safer and associated to lower rates of complications if
performed by experienced operators.
2. Justification
As already mentioned, this study aims at comparing the incidence of iASD as
well as its clinical significance between RF and cryoenergy catheter ablation in
patients presenting with AF at 1-year follow up. PVI by catheter ablation is a
highly effective therapy for the treatment of this arrhythmia, especially in those
who are refractory to antiarrhythmic drug therapy(47,48). Traditionally, these
procedures are performed with a “point by point” ablation technique by means
of RF energy(47). However, in the last years the use of novel technologies such
as CB ablation has grown rapidly on the grounds of improving the effectiveness
in producing PVI(31).
During the procedure, either cryoballoon ablation or RF, transseptal pucture is
the first step in order to reach left atrium. This transseptal puncture might
hypothetically lead to permanency of IASD(10,12–14,43,49) .
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 16
The literature on this topic is sparse, but iASD is a common complication after
PVI. The most worrying clinical consequence is paradoxical embolism,
secondary to right-to-left shunting. Although, the most typical shunting direction
found in these patients is left-to-right shunting, this complication should not be
underestimated. To our knowledge, there are no studies so far comparing the
incidence of iASD by using either cryoablation or RF ablation.
Our final challenge is to be able to make up with the safest possible and
curative technique to treat our patients.
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 17
PART 2: STUDY
2.1 Hypothesis
IASD has been reported as a complication of transseptal puncture, which is the
first step of every AF ablation procedure to access left atrial.
Several
suggestions related to iASD have been made:
-
It is believed that larger-diameter sheath might result in a higher rate of
iASD, and the diameter of cryoballoon is 15F vs 8.5F in RF ablation. So, it
should be found differences in the incidence of iASD depending on the
technique used, being more incident in the Cryoballoon ablation group.
-
It is suggested that in most of the iASD, the shunting found is left to right,
and the paradoxical embolism, which is the most important concern
related to iASD happens when it takes place right-to-left shunting. This
means that no adverse clinical events should be found.
2.2 Objective
Mean objectives
This study aims to compare the incidence and clinical significance of iatrogenic
Atrial Septal Defect at 1-year follow-up in 127 patients who underwent
transseptal catheterization with either cryoballoon ablation or radiofrequency
catheter ablation.
Secondary objective
- To investigate if there are any risk factors associated to the persistence of
IASD.
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 18
2.3 Material and methods
2.3.1 Study design
It is a retrospective cohort study in which we observe and compare the
incidence and clinical significance of persisent iASD in patients who underwent
RF ablation or cryoablation for PVI.
2.3.2 Participants
The study population was made up of individuals affected by drug resistant
paroxysmal or early persistent AF from the Heart Rhythm Management Center,
Free University of Brussels, who have undergone PV isolation by means of CB
ablation or RF ablation and a transesophageal echocardiography (TEE)
examination during post ablation follow-up between January 2008 and
December 2012.
127 patients from the database at the hospital who
accomplished these characteristics were consecutively included in our
retrospective analysis.
2.3.3 Inclusion and exclusion criteria
Exclusion criteria to the ablation procedure consisted of inability to undergo
TEE, the presence of an LA thrombus at the preprocedural TEE, severe
uncontrolled hcceart failure, contraindications to general anesthesia, or severe
comorbility. Patients with a patent foramen ovale (PFO) prior to the index
procedure were excluded from our analysis.
Inclusion criteria included patients affected by drug resistant paroxysmal or
early persistent AF prior to the ablation procedure who underwent PVI by
means of RF or CB ablation and a TEE examination during post ablation followup.
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 19
2.3.4 Sample size
A non-probabilistic consecutive sampling method has been used. All 127
patients who underwent PVI and a TEE examination during postablation follow
up were the target population.
Even though the calculation of the sample size depends on the margin of error
(0.05), on condifence interval (CI) (95%) and on the estimate rate of the study
outcome, the latter is difficult to calculate in our case because there are a few
studies about ASD in AF ablation. A previous study by Sieira et al at reported a
20% incidence of IASD at 1 year after cryoballoon ablation(10). However, there is
a great variability in the RF studies. Anselmino et al reported 5.6% at 1 year
with one transseptal puncture(43), Rilling et al 3.7% at 1 year with double
transeptal puncture(12), Hammerstingl 18% at 9 months with single TS puncture
and 0% with double TSP(13).
If we assume a rate of 10% incidence in the total population of CB and RF
patients with a margin of error of 5% and CI of 95%, we calculate that we need
a sample of 138 patients. In our study, the sample is a bit lower (127 patients),
however the margin of error is acceptable (5.2%). Therefore, increasing the
population might hypothetally increase the precision but might not change
substantially the incidence of IASD.
From these 127 patients, 82 patients belong to RF group and 45 patients to CB.
So, assuming a IASD incidence of 5% in RF procedures and 25% in cases of
CB according to literature, the power of the study is 83%.
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 20
2.3.5 Variables and measurements
Independent variable
Type of Intervention- catheter diameter
-
Radiofrequency ablation (French)
-
Cryoballoon ablation (French)
Dependent variable
-
Presence
of
iASD
evaluated
echocardiography.
-
Clinical significance of IASD.
Associated variables
Sociodemographic variables
-
Sex (Male/Female)
-
Date of birth (years)
Clinical variables
-
Paroxysmal AF
-
Duration of symptoms
-
Arterial hypertension (yes/no)
-
Dyslipidemia (yes/no)
-
Diabetes Mellitus (yes/no)
-
Body mass index (kg/m2)
-
Structural heart disease (yes/no)
o Coronary artery disease
o Valvular cardiomyopathy
o Hypertophic cardiomyopathy
o Dilated cardiomiopathy
by
using
transesophageal
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 21
o Absent
-
Previous right atrial flutter ablation (yes/no)
-
CHADS-VASC score
Echocardiographic variables
-
Left atrial diameter (mm)
-
Left ventricular ejection fraction
-
Time to TEE (months)
Identification data
At baseline, sociodemographic data from each participant were collected.
Echocardiographic examination
All patients underwent TEE before the procedure, along with a transthorcacic
examination (TTE). In particular, left atrial and left ventricular dimensions as
well as valve function and ejection’s fraction was examined. Interatrial septum
with 2D and color Doppler flow was examined from multiple views. Atrial septal
defect was defined as interatrial shunt confirmed by Doppler flow beside the
fossa ovalis but not fulfilling the criteria for patent foramen ovale (PFO)(50).
Preprocedural CT scan
The anatomical aspect of the pulmonary veins is extremely variable and it is of
utmost importance in the setting of PVI. Therefore, CT scans were performed
prior to ablation in order to analyze the left atrial anatomy.
Ablation procedure: Cryoballoon Ablation
The CB ablation procedures were performed under general anesthesia.
Following a single transseptal puncture, a circular mapping catheter (CMC)
(Lasso, Biosense Webster, Inc., Diamond Bar, CA, USA) or a 20-mm diameter
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 22
octapolar inner lumen mapping catheter (ILMC) (Achieve, Medtronic, MN, USA)
were used to obtain baseline electrical information. Following the mapping, a 23
mm or 28 mm CB (Arctic Front, Medtronic) was inserted over the ILMC or the
guidewire in the left atrium (LA). The choice of the balloon diameter was
determined by the LA and PV anatomy observed on the preprocedural CT scan.
However, whenever possible, the larger diameter CB was preferred. Once
inflated and wedged in the PV ostium, dye was injected and vessel occlusion
was evaluated according to a semiquantitative grading ranging from grade 0
(very poor occlusion) to grade 4 (perfect occlusion) in 2 different fluoroscopic
projections. For each vein, cryoablation consisted of a minimum of 2
applications lasting 4 minutes each. In order to avoid phrenic nerve palsy, a
complication observed during right-sided PVs ablation with CB, a quadripolar
catheter was inserted in the superior vena cava and diaphragmatic stimulation
was achieved by pacing the ipsilateral phrenic nerve with a 1200 ms cycle at an
output of 20 mA. PV isolation was assessed either with the CMC or ILMC
immediately and 20 minutes after the procedure. During the whole procedure,
activated clotting time was maintained between 250 and 350 seconds with
supplements of heparin infusion, as required.
Ablation procedure: Radiofrequency ablation
Radiofrequency ablation was performed as follows. After having accessed the
left atrium with a double transseptal puncture, a 70 UI/kg heparin intravenous
bolus was given. A selective PV angiogram was performed to assess all PV
ostium positions. A CMC (Lasso; Biosense Webster Inc., Diamond Bar,
California) was positioned into the proximal portion of the PV ostium to get
baseline electrical information. Then an electroanatomic map of the left atrium
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 23
was performed with a non fluoroscopic navigation system (CARTO; Biosense
Webster Inc.). Radiofrequency ablation was performed with an open irrigated
cool tip 3.5-mm catheter (NaviStar ThermoCool; Biosense Webster Inc.) in a
power-controlled mode with a power limit of 35 W and at a maximum
temperature of 48°C. Each application lasted a maximum of 60 seconds. Power
was reduced to 25 W during ablation of LA posterior wall to prevent esophageal
injury. The ablation strategy consisted in creating contiguous focal lesions at a
distance of > 5 mm from the ostia of the PVs resulting in circumferential lines
around ipsilateral PVs. During the whole procedure, activated clotting time was
maintained at > 250 seconds by supplementing heparin infusion
Postprocedural management
All patients were dismissed the day following ablation. A TTE was performed in
all individuals in order to exclude postprocedural pericardial effusion. Therapy
with low molecular weight heparin (LMWH) was started the same day following
ablation. Oral anticoalgulation (OAC) was started the day following the
procedure. Patients were dismissed on both OAC and LMWH. When a target
INR of 2-3 was reached, LMWH was stopped and only OAC was continued.
OAC was continued for at least 3 months after the procedure. Antiarrhythmic
therapy was administered for 3 months following the procedure and
discontinued if the patient was free of AF relapse.
Follow-up
Clinical follow-up consisted in physical examinations, ECG and 24- hour Holter
recording performed at 3, 6, 12 months and every 6 months after the first year.
A blanking period of 3 months was considered for the study. Atrial fibrillation
recurrence during the blanking period was taken into consideration for final
analysis.
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 24
2.3.6 Statistical analysis
Data analyses are primarily focused on the baseline characteristics in both
groups of patients to make them comparable. Next, we evaluated the
procedural time depending on the technique used. Later, we analysed the iASD
found, as well as, the diameter, and compared the iASD incidence according to
the technique used. Finally, we tried to find predictors for the IASD persistence.
Data are given as mean and standard deviation (SD) for quantitative variables
(age, duration of symptoms, CHADS-VASC score, body mass index, LA
diameter, left ventricular ejection fraction, time to TEE), or as absolute values
and percentages for qualitative values (gender, Paroxysmal AF, arterial
hypertension, dyslipidemia, diabetes mellitus, structural heart disease, previous
right atrial flutter ablation, IASD), as appropriate, with a 95% confidence
interval.
A bivariate analysis has been made, in which continuous variables were
compared using the Student’s t-test or Mann-Whitney as appropriate and
categorical variables were compared using chi-square or Fisher test. A p value
of <0.05 was deemed statistically significant. Statistical analyses were
conducted using SPSS software (SPSS v21, Chicago, IL, USA).
2.4 Ethical considerations
The Ethics Committee of the Investigation centre approved the protocol.
The protocol was carried out in accordance with the ethical principles for
medical
research
involving
human
subjects
established
by
Helsinki’s
Declaration, protecting the privacy of all the participants as well as the
confidentiality of their personal information.
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 25
All patients gave written informed consent.
2.5 Results
Baseline characteristics
A total of 127 patients (92 males, 72%; mean age 60±11 years) were finally
considered in our analysis. Specifically, 82 patients (58 males, 71%; mean age
61±9 years) having undergone RF ablation as index procedure and 45 patients
(34 males, 76%; mean age 58±14 years) treated by CB ablation as first
procedure. Baseline characteristics of both groups are listed in Table 1. No
statistical differences between the 2 groups were found in terms of baseline
population characteristics. Paroxysmal AF was documented in 54 patients in
the RF group and 34 patients in the CB group (66% vs 76%, respectively;
p=0.3) prior to the procedure. Mean time of AF in the whole study population
was 40.9±50.6 months (44.2±48.1 months in RF group vs 34.9±54.9 months in
CB group; p=0.4).
Preprocedural TEE
All patients underwent a TEE the day before procedure. Similar LA diameter
(46±6mm in RF group vs 45±7mm in CB group; p=0.3) and mean left ventricular
ejection fraction (58±10% in RF group vs 59±9% in CB group; p=0.8) were
observed in both groups. Echocardiographic features are shown in Table 2.
Procedural parameters
Procedural time was significantly shorter in the CB group (181±53 minutes vs
109±56 minutes; p <0.001). Similar fluoroscopy times were observed between
the 2 ablation procedures (31±20 minutes in RF group vs 28±14 minutes in CB
group; p=0.5). In all patients, PVs were completely isolated at the end of
procedure. In the CB ablation group, the 23 mm and 28 mm CB were used in 3
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 26
and 42 patients, respectively. Mean minimal temperatures were -53.2±10.2°C in
the left superior PV (LSPV), -49.3±9.9°C in the left inferior PV (LIPV), 51.6±10.1°C in the right superior PV (RSPV), and -48.8±16.8°C in the right
inferior PV (RIPV). After a mean 2.2 applications, veins were isolated. In 3
patients (right inferior PVs in 2 and left inferior PVs in 1) who underwent CB
ablation, a focal touch-up with either a focal-tip cryocatheter (Freezor Max;
CryoCath Technologies Inc., Montreal,Quebec, Canada) or an irrigated-tip RF
catheter (NaviStar ThermoCool; Biosense Webster Inc.) was delivered. In the
RF group, mean energy application time was 45±7 min/patient. During the CB
ablation procedure, transient phrenic nerve palsy occurred in 3 patients (6.7%)
and completely reverted in all cases before the end of procedure. In the RF
group, one case of transient ST elevation secondary to air embolism (1%) and
one case of pericardial tamponades requiring immediate drainage (1%)
occurred.
Repeat TEE
During the follow up, an IASD was found in a total of 18 patients (14.2%).
Particularly, an IASD was detected in 10 patients (22.2%) after CB ablation and
in 8 patients (8.5%) after RF ablation procedure (p=0.03). In the whole study
population, mean maximum and minimum IASD diameter were 0.54±0.27 cm
and 0.44±0.26 cm, respectively. Specifically, mean maximum and minimum
IASD dimension were 0.44±0.11 cm and 0.35±0.10 cm, respectively, in the RF
ablation group and 0.60±0.33 cm and 0.50±0.33 cm, respectively, in the CB
ablation group (p=0.2 for the maximum IASD dimension and p=0.3 for the
minimum IASD dimension). All cases of IASD presented left to right interatrial
shunt. In the study population, the main reason for performing a second TEE
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 27
was a repeat PV isolation procedure for AF recurrence (n=112, 88.2%) followed
by external cardioversion (ECV) in 12 patients (9.4%) and percutaneous LA
appendage closure procedure in three patients (2.4%). In the RF group, a
second TEE was performed for a repeat PV isolation procedure in 74 patients
(90.2%) and for an ECV in 8 patients (9.8%). In the CB group, the main reason
for performing a second TEE was a repeat PV isolation procedure due to AF
recurrence (n=38, 84.4%; p=0.3); other indications for repeat TEE were external
cardioversion (ECV) in 4 patients (8.9%; p=0.9) and percutaneous LA
appendage closure procedure in three patients (6.7%; p=0.02). In the whole
study population, the mean time from index ablation procedure to repeat TEE
was 11.6±7.8 months. Specifically, the mean time from index procedure to
repeat TEE was 11.9±7.8 months in the RF ablation group and 11.3±7.9
months in the CB ablation group (p=0.7). Six patients with IASD (4 in the CB
group, 40%, and 2 in the RF group, 29%; p=0.6) received oral anticoagulation
therapy during the follow up after the blanking period due to AF recurrence. No
predictors of IASD were found in both groups (Table 3).
Follow up
Freedom of AF
After a mean total of 212 ablation procedures, 104 patients (93.7%) were free of
AF at 18.9±15.3 months. The success rate for repeat RF ablation procedures
was 90.5% (67 patients) and 97.4% (37 patients) for repeat CB procedures
(p=0.18). In the RF group, among 8 patients having undergone ECV, 6 (75%)
were free of AF at a mean follow up of 13.5±8.3 months; of the 4 patients
having undergone ECV in the CB group, 3 (75%; p=ns) were free of AF at a
mean follow up of 12.0±11.6 months. The 3 patients having undergone LA
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 28
appendage closure secondary to the development of chronic AF and contra
indications to oral anticoagulation therapy did not present adverse events
during a mean follow up of 20.3±15.5 months.
Adverse events
Following the index procedure, no patients in both groups with persistent IASD
presented a cerebral event.
In the CB group, one patient without IASD experienced an ischemic stroke
without neurological sequelae after 52 months from the initial CB ablation
procedure; this patient was 63 years old at the time of the stroke, in sinus
rhythm and he wasn’t doing OAC therapy. In the RF group, one patient without
IASD suffered an ischemic stroke secondary to middle cerebral artery occlusion
after 21 months from the initial RF ablation procedure; this patient was 64 years
old at the time of stroke, in a persistent recurrence of AF and he was doing
OAC therapy.
2.6 Discussion
The main finding of our study is that the incidence of IASD at 1-year is
significantly higher following CB procedures if compared to RF ablation. To the
best of our knowledge, this is the first study comparing the incidence of IASD
between double transseptal conventional RF and CB ablation at 1-year follow
up.
IASD following CB ablation
The persistence of IASD following CB ablation has been analyzed in 2 previous
studies(10,14). Chan et al(14) identified IASD in 38% of patients at 6 months and
31% at 9 months in 13 consecutive patients having undergone PVI using CB
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 29
ablation. Our group recently reported a 20% of IASD persistence in a series of
39 consecutive patients after 1 year from CB ablation(10). Our current results are
consistent with these previous reports identifying IASD in 22.2% of patients
having undergone CB ablation at 1-year follow up with similar defect diameters
(0.60x0.50 cm).
IASD following RF ablation
Some previously published reports investigated also the incidence of IASD
following PVI by means of RF technology(12,13,43,51). Obel et al reported an IASD
incidence of 6.5% in patients having undergone PVI procedure achieved by
double TS puncture after a follow-up period of 33 weeks(51). Rillig et al found
only 1 patient (3.7%) with a detectable IASD after 12 months from PVI(12).
Another study analyzed the persistence of IASD after a single TS puncture with
passage of 2 electrophysiological catheters into the LA or double TS puncture
reporting an incidence of 19% at 9 months; all defects were observed in the
single TS puncture group(13). Recently, Anselmino and co-workers also found a
percentage of 5.6% of patients presented an IASD after RF ablation using
single TS puncture at a median follow up of 12 months(43). Our results are
consistent with the literature showing a relatively low incidence of IASD (8.5%)
following RF ablation achieved by double TS puncture.
The incidence of IASD between RF and CB ablation groups
The higher incidence of IASD in the CB ablation group might be explained by
the larger sheath diameter (15F) compared with smaller sheats (8.5F) advanced
through a double TS puncture in the RF ablation procedure. The larger outer
diameter of the sheath inserted through the single TS puncture might be
hypothetically more traumatic for the interatrial septum, although IASD
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 30
diameters did not significantly differ between both groups. Of note, IASD
dimensions following CB ablation were larger than those following RF ablation
(0.60x0.50 cm vs 0.44x0.35 cm).
Clinical consequences
As described previously, the clinical significance of persistent IASD has not yet
been well-defined. In this study no neurological complications related to IASD
were observed during the follow-up period. Luckily, no right to left interatrial
shunts were observed, which seem to be significantly more related to the
paradoxical embolism. Predisposing morphological characteristics for the
occurrence of paradoxical embolism have been extensively studied and
characterized such as big diameters, spontaneous right to left atrial shunt and
aneurismatic septum(52). In our series, the IASD found after PVI procedures did
not fulfil this criteria. Otherwise, risks related to this complication should not be
underestimated.
Echocardiographic follow up and IASD management
Although TEE examination was used in our study to assess IASD, less invasive
methods might be alternatively used to identify IASD with similar accuracy
during the follow up(53,54). Transthoracic echocardiogaphy with agitated saline
injection (ASI) and provocative maneuvers such as Valsalva have been found
to be equally reliable to diagnose an atrial septal defect. Moreover, TTE
including novel 3D technologies might offer highly reliable measurements of
IASD dimensions unless extremely small (< 2 mm)(55,56). Therefore, it might be
advisable to perform TTE with ASI or alternatively 3D technology in the early
phases of the follow up. Patients presenting IASD might undergo regular
echocardiographic follow up in order to examine the behavior of the IASD over
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 31
the time in terms of spontaneous reduction in dimensions. As the literature
dealing with IASD after PVI using RF or CB ablation is still limited, it might be
difficult to identify which patients would benefit of IASD closure. Thus, the latter
should be performed according to current guidelines(57). No risk factors were
found to be associated with IASD (Table 3).
2.7 Limitations
In regard to the limitations of this study, first, it should be considered that this
study has a observational design. Besides, as all data have been collected in a
single center, the results should not be generalized. The small number of
patients and limited follow-up represent also limitations of our study. Moreover,
we did not perform intermediate TEE examinations, which would have helped
us in evaluating the rate and dimensions of IASD at different stages of the
follow-up. All patients received OAC for at least 3 months after the procedure.
This fact may also affect the occurrence of systemic embolism. No specific
imaging technique has been used to rule out silent cerebral emboli. The use of
this approach would have allowed us to make a more accurate diagnosis of
asymptomatic cerebral events(58). Finally, TEE was performed without ASI
(agitated saline injection) or Valsalva maneuvers in all patients. Performing the
latter might have optimized the assessment of this complication(59).
2.8 Conclusion
The incidence of IASD at 1-year follow up following PVI was significantly higher
in the CB ablation group compared with RF ablation group (22.2% vs 8.5%;
p=0.03). Dimensions of IASD did not significantly differ between both groups.
Only left to right atrial shunt could be observed. No clinical or procedural
predictors of IASD were found in our series of patients. Although no adverse
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 32
clinical events were recorded in patients with persistence of IASD, this
complication should not be underestimated and systematic echocardiographic
examinations might be advised in all individuals exhibiting this finding. Further
studies with larger population and longer follow-up might be required to confirm
our findings.
2.9 Cronogram
ACTIVITY
July 2014
August 2014
September
2014
October
2014
2015
Ethical
committee
Bibilography
research
Protocol
elaboration
Data
collection
Statistical
analysis
Results
Final article
elaboration
Publication of
data
Activity
Investigators
Bibliography research
Marta Soriano
Protocol elaboration
Marta Soriano
Data collection
Juan Sieira, Giacomo Mugnai and
Marta Soriano
Results analysis
HRMG (Heart Rhythm management
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 33
group)
Final article elaboration
Giacomo
Mugnai,
Gian-Battista
Chierchia and Marta Soriano
Publication of data
HRMG (Giacomo Mugnai, Juan Sieira,
Giuseppe
Ciconte,
Ghazala
Irfan,
Yukio Saitoh, Burak Hunuk, Kristel
Wauters,
Claudio
Tondo,
Giulio
Molon, Carlo de Asmundis, Pedro
Brugada, Gian-Battista Chierchia and
Marta Soriano)
2.10 Budget
Activity
Costs
Statistical analysis
1,000 €
Publication costs
2,000 €
Diffusion of the data
2,050 €
TOTAL
5,050 €
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 34
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TABLES
Table 1. Comparison of baseline characteristics between RF and CB
ablation procedures
RF ablation
CB ablation
(n=82)
(n=45)
Age, years
61±9
58±14
0.2
Men, %(n)
71% (n=58)
76% (n=34)
0.6
Paroxysmal AF, %(n)
66% (n=54)
76% (n=34)
0.3
44±48
35±55
0.4
Arterial hypertension, %(n)
61% (n=50)
44% (n=20)
0.07
Dyslipidemia, %(n)
44% (n=36)
42% (n=19)
0.8
Diabetes mellitus, %(n)
12% (n=10)
2% (n=1)
0.06
CHADS-VASC score
1.7±1.4
1.4±1.2
0.2
Body mass index
27.7±4.5
26.6±3.7
0.2
12% (n=9)
4% (n=2)
0.2
4% (n=3)
2% (n=1)
0.7
1% (n=1)
4% (n=2)
0.2
1% (n=1)
2% (n=1)
0.7
83% (n=68)
87% (n=39)
0.6
26% (n=21)
24% (n=11)
0.9
Duration of symptoms, months
P-value
Structural heart disease:
-
Coronary artery disease, %(n)
-
Valvular cardiomyopathy, %(n)
-
Hypertrophic cardiomyopathy, %(n)
-
Dilated cardiomyopathy, %(n)
-
Absent, %(n)
Previous right atrial flutter ablation, %(n)
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 41
Table 2. Comparison of echocardiographic characteristics between the 2
groups
RF ablation
CB ablation
(n=82)
(n=45)
Left atrial diameter, mm
46±6
45±7
0.3
Left ventricular ejection fraction, %
58±10
59±9
0.8
11.9±7.8
11.3±7.9
0.7
Time to TEE, months
P-value
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 42
Table 3. Predictors of IASD persistence in the study population and in
both RF and CB groups
Study Population
RF ablation group
CB ablation group
No IASD
IASD
P
No IASD
IASD
P
No IASD
IASD
P
59.6±11.
59.2±10.
0.9
60.6±9.1
59.9±8.2
0.5
57.7±14.
58.7±12.
0.8
2
4
6
1
Sex, (% male)
70.9
82.3
0.3
70.7
71.4
0.9
71.4
90.0
0.2
Paroxistic, %
69.1
70.6
0.7
64.0
85.7
0.2
80.0
60.0
0.2
HTA, %
55.4
52.9
0.9
61.3
57.1
0.8
42.9
50.0
0.7
Dyslipidemia, %
44.5
35.3
0.5
45.3
28.6
0.4
42.9
40.0
0.9
9.1
5.9
0.7
12.0
14.3
0.9
2.9
0.0
0.6
LA diameter, mm
45.7±6.9
45.6±5.6
0.9
46.1±6.6
46.9±6.8
0.8
45.0±7.5
44.7±4.8
0.9
LVEF, %
58.4±9.4
63.5±8.1
0.1
58.9±9.5
64.6±9.4
0.1
57.5±9.4
62.8±7.5
0.1
Time to TEE, months
11.7±7.5
12.2±9.8
0.8
11.9±7.6
12.5±10.9
0.8
11.2±7.5
11.9±9.6
0.8
Age, years
DM, %
IASD: iatrogenic atrial septal defect, HTA: arterial hypertension, LA: left atrial, LVEF: left ventricular
ejection fraction, TEE: transesophageal echocardiography
ON THE WAY TO CURE AF. “IATROGENIC ATRIAL SEPTAL DEFECT AFTER ABLATION PROCEDURES”. 43